Antagonism of Metabotropic Glutamate 1 Receptors Attenuates Behavioral Effects of Cocaine and Methamphetamine in Squirrel Monkeys

Abstract

Within the group I family of metabotropic glutamate receptors (mGluRs), substantial evidence points to a role for mGluR5 mechanisms in cocaine's abuse-related behavioral effects, but less is understood about the contribution of mGluR1, which also belongs to the group I mGluR family. The selective mGluR1 antagonist JNJ16259685 [(3,4-dihydro-2H-pyrano-[2,3-b]quinolin-7-yl)-(cis-4-methoxycyclohexyl)-methanone] was used to investigate the role of mGluR1 in the behavioral effects of cocaine and methamphetamine. In drug discrimination experiments, squirrel monkeys were trained to discriminate cocaine from saline by using a two-lever, foodreinforced operant procedure. JNJ16259685 (0.56 mg/kg) pretreatments significantly attenuated cocaine's discriminative stimulus effects and the cocaine-like discriminative stimulus effects of methamphetamine. In monkeys trained to self-administer cocaine or methamphetamine under a second-order schedule of intravenous drug injection, JNJ16259685 (0.56 mg/kg) significantly reduced drugreinforced responding, resulting in a downward displacement of dose-response functions. In reinstatement studies, intravenous priming with cocaine accompanied by restoration of a cocaine-paired stimulus reinstated extinguished cocaine-seeking behavior, which was significantly attenuated by JNJ16259685 (0.56 mg/kg). Finally, in experiments involving food rather than drug self-administration, cocaine and methamphetamine increased the rate of responding, and the rate-increasing effects of both psychostimulants were significantly attenuated by JNJ16259685 (0.3 mg/kg). At the doses tested, JNJ16259685 did not significantly suppress food-reinforced behavior (drug discrimination or fixed-interval schedule of food delivery), but did significantly reduce speciestypical locomotor activity in observational studies. To the extent that the psychostimulant-antagonist effects of JNJ16259685 are independent of motor function suppression, further research is warranted to investigate other mGluR1 antagonists for potential therapeutic value in psychostimulant abuse.

Dyskinesias and impulse control disorders in Parkinson's disease: From pathogenesis to potential therapeutic approaches

“…The mGluR5 antagonists MPEP and MTEP reduce the selfadministration of addictive substances (i.e. nicotine, amphetamine, cocaine, morphine or alcohol) in rats and mice (Hodge et al, 2006;Kenny et al, 2003;Martin-Fardon et al, 2009;Osborne and Olive, 2008;Paterson et al, 2003;Schroeder et al, 2005), and the mGluR1 antagonist (3,4-dihydro-2H-pyrano-[2,3-b]quinolin-7-yl)-(cis-4-methoxycyclohexyl)-methanone (JNJ16259685) ameliorates the behavioral effects of cocaine and methamphetamine in squirrel monkeys and alcohol intake in rats (Achat-Mendes et al, 2012;Besheer et al, 2008). Other mGluR1 antagonists such as NAM-EMQMCM and CPCCOEt either did not change (Schroeder et al, 2005) or reduced ethanol (Lominac et al, 2006) self-administration in rodents.…”

Modulatory effects of Ampicillin/Sulbactam on glial glutamate transporters and metabotropic glutamate receptor 1 as well as reinstatement to cocaine-seeking behavior

“…Studies revealed that treatment with selective mGluR1 antagonists reduced cocaine-seeking behavior in monkeys (28), and reduced psychomotor sensitization in rodents (29, 30). In addition, a study showed that mGluR1 antagonist blocked cocaine-induced CPP (31).…”

Dopamine D3 receptors contribute to methamphetamine-induced alterations in dopaminergic neuronal function: Role of hyperthermia

“…Although several neurotransmitter systems are presumably involved in the reinforcing (Achat-Mendes et al, 2012; Munzar et al, 1999) and neurochemical (Eisch et al, 1996; Stephans and Yamamoto, 1994) effects of methamphetamine, there has been a large focus on dopamine systems (Koob and Volkow, 2010). Methamphetamine use can produce both acute and long-term changes in dopaminergic neurons, as demonstrated in rodents (Hadlock et al, 2010; Metzger et al, 2000), non-human primates (Melega et al, 1997), and humans (McCann et al, 1998; Wilson et al, 1996).…”